Neonatal screening for Kernicterus External review against programme appraisal criteria for the UK National Screening Committee (UK NSC)

Version: 3

Bazian Ltd July 2011

The UK NSC advises Ministers and the NHS in all four UK countries about all aspects of screening policy. Its policies are reviewed on a 3 yearly cycle. Current policies can be found in the policy database at http://www.screening.nhs.uk/policiesand the policy review process is described in detail at http://www.screening.nhs.uk/policyreview Template v1.2, June 2010 UK NSC External Review

Contents

Introduction ...... 3 Appraisal against UK NSC Criteria ...... 5 Conclusions ...... 34 Implications for policy ...... 35 Implications for research ...... 35 Methodology ...... 36 Quality ...... 37 References ...... 42

Page 2 UK NSC External Review

Introduction Kernicterus is a very rare complication of neonatal unconjugated hyperbilirubinaemia. In kernicterus high levels of bilirubin cause brain damage leading to neurological symptoms such as hearing loss and cerebral palsy and can in some cases be fatal. Screening for hyperbilirubinaemia has been suggested as a means of preventing kernicterus. However there is uncertainty about how to define a high risk level of hyperbilirubinaemia given that bilirubin levels are distributed continuously and are affected by gestation at birth and time since birth. Therefore any value chosen as a cut-off point would need to take these and other clinical factors into account. Furthermore, the risk factors for progression from hyperbilirubinaemia to kernicterus also remain unclear and only a small proportion of neonates with high levels of unconjugated bilirubin will develop kernicterus.

The current NSC policy, last reviewed in February 2007 is that screening should not be offered. This policy decision was based on a report by Newman and Maisels published in 2006.1 This report said that bilirubin levels might be used to identify neonates that warrant monitoring and close follow up, for those who require immediate treatment or a combination of these. The report looked at screening tests including visual inspection for jaundice, transcutaneous bilirubin measurements and measurements of serum bilirubin levels in a blood sample. Treatments to reduce bilirubin levels are available. In the report the authors say that a high number of babies would need to be treated to prevent one case of kernicterus, not due to the lack of efficacy, but rather because of the rarity of kernicterus and the high incidence of neonatal jaundice with generally benign natural history. In their report they suggested that a decision on universal bilirubin screening be deferred until: 1. Adequate standardisation of total serum bilirubin measurements have been accomplished 2. The cases reported to the British Paediatric Surveillance Unit have been analysed (e.g., with a “root cause “analysis) 3. A system of mandatory reporting of elevated bilirubin levels is in place to quantify the extent of the problem at baseline and monitor progress 4. Ready access to transcutaneous bilirubin measurements and TSB measurements among in- and outpatients has been assured. Since the Newman and Maisels report was published, NICE has published clinical guidelines on the management of neonatal jaundice.2 The guidelines have systematically reviewed the evidence for recognition and treatment of clinically significant jaundice and have produced a treatment algorithm for neonates presenting with jaundice. The systematic search used by NICE included articles published up to June 2009. Additionally a prospective cohort study of cases presenting with severe hyperbilirubinaemia in the UK and Ireland, supported by the British Paediatric Surveillance Unit (BPSU) and a report from the US pilot kernicterus registry have helped to better define the natural history of kernicterus.

It is important to highlight that the NICE guidelines include evidence-based but non-mandatory recommendations for discharge of new-borns after birth, the detection and treatment of

Page 3 UK NSC External Review jaundice. The recommendations have not specifically addressed how cases of kernicterus can be prevented or whether routine screening of babies for risk factors for kernicterus is appropriate. Management of jaundice involves lowering bilirubin levels and diagnosing the cause of the jaundice which may require additional ongoing treatments, largely at the point of discharge. Management is not a screen for subsequent complications of hyperbilirubinaemia such as kernicterus although management of jaundice when it presents may prevent some cases of kernicterus. The aim of this review is to assess whether all newborns should be screened for their risk of developing kernicterus. To review a potential screening programme it is necessary to assess the evidence for tests and treatments for conditions and we have included a description of the management and treatment recommendations for neonatal jaundice outlined by NICE and the evidence base which had led to these recommendations where considered relevant. Additionally, these guidelines have been used to give an indication of current practice, with the caveat that as these are non-mandatory it is unclear how widely they have been adopted.

In this report we have used evidence published from 2006 to January 2011 to update the Newman and Maisels assessment on screening for kernicterus against the National Screening Committee (NSC) criteria for appraising the viability, effectiveness and appropriateness of a screening programme. We have focused on evidence relating to newborn screening for clinically significant bilirubin levels which require immediate treatment and risk of clinically significant hyperbilirubinaemia and kernicterus.

We have assessed whether there is any evidence for an additional benefit or additional harms or costs from implementing a screening programme to prevent kernicterus using bilirubin levels in all babies measured in a blood sample or transcutaneous measurements. In particular looking at whether such a programme could reasonably be expected to prevent additional cases of kernicterus further to the neonatal jaundice management strategy outlined by NICE.

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Appraisal against UK NSC Criteria These criteria are available online at http://www.screening.nhs.uk/criteria. We have made the provisional summary statements met, not met, partly met or not applicable after each criteria. These are provisional suggestions and should be reviewed in the context of all the evidence available.

1. The condition should be an important health problem Hyperbilirubinaemia is an accumulation of bilirubin in the blood, a breakdown product of haem from red blood cells. Bilirubin is yellow and if blood levels rise can cause jaundice, a yellow colouration of the skin and whites of the eyes. 3 it has been estimated that approximately 60% of term babies and 80% of preterm babies develop jaundice in the first week of life, and about 10% of breastfed babies are still jaundiced at one month of age.2 Hyperbilirubinaemia can cause kernicterus, a brain-damaging condition caused by unconjugated bilirubin crossing the blood brain barrier which has symptoms including manifestations of cerebral palsy and deafness. Besides kernicterus, hyperbilirubinaemia can cause other conditions such as deafness without cerebral palsy. This updated review assesses the evidence for screening for kernicterus rather than hyperbilirubinaemia.

Jaundice in the first 24 hours of life is rare. The NICE neonatal jaundice guideline provides a treatment algorithm for jaundice observed within the first 24 hours and up to 72 hours after birth. After discharge from hospital, follow up post natal care can be carried out in the home for the majority of women and their babies. Infants receive blood spot screening when they are five to eight days old and this is a further contact with a health professional which all babies should receive. Hyperbilirubinaemia is a symptom of various pathologies which are described below and the cause of the hyperbilirubinaemia affects when it will present. The NICE management recommendations advise that babies presenting with jaundice in the first 24 hours should have their bilirubin levels measured and be referred for urgent medical review to exclude pathological cases of jaundice. In the majority of babies jaundice arises without an underlying disease. This is called ‘physiological jaundice’. Breast fed babies are more likely than bottle fed babies to develop jaundice within the first week of life, but breast feeding, breast milk and physiological jaundice are generally harmless and cessation of breast feeding is not recommended.2 Physiological jaundice usually appears between day 2 and 3, begins to disappear towards the end of the first week of life and should be resolved by 10 days after birth.

The underlying pathology of some cases of jaundice may include blood group incompatibility which can lead to haemolysis and other causes of haemolysis, sepsis, bruising and metabolic disorders. Deficiency of the enzyme glucose-6-phospate dehydrogenase (G6PD), delay in the maturation of the enzyme that conjugates bilirubin (UDP Glucuronosyltransferase a condition called Gilbert syndrome) or deficiency in liver enzymes that allow usual metabolic breakdown of bilirubin (Rare Orphan disease Crigler-Najjar Syndrome). Jaundice may be caused by congenital obstruction of or malformations of the biliary system, such as biliary atresia, in which case the bilirubin is conjugated.2

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Bilirubin can exist in a conjugated (conjugated with glucuronic acid in the liver) or unconjugated form. Hyperbilirubinaemia of conjugated bilirubin is less common than hyperbilirubinaemia of unconjugated bilirubin1 (as in newborns almost all bilirubin is unconjugated)and may arise following hypothyroidism, infections, haemolysis and biliary atresia. In addition to jaundice accumulation of conjugated bilirubin may be accompanied by other signs in infants such as , light stools, or dark urine.1 As kernicterus, also known as acute bilirubin encephalopathy (ABE), is rare its natural history is not well defined; the early clinical signs of kernicterus may be insidious and may be missed by clinicians. In the process of establishing a national reporting system for kernicterus in the USA and to define eligibility for a pilot kernicterus registry a consensus was reached for the clinical diagnosis of both acute stage kernicterus and chronic post-icteric sequelae.4 Signs of kernicterus were determined to include tone abnormalities such as hypotonia alternating with progressive hypertonia of extensor muscles, tilting back of the head (retrocollis), rigidity and arching of the back (opisthotonus). Other symptoms are drowsiness and lethargy which may manifest as decreased feeding and irritability. The baby may also have a high pitched cry. The pilot kernicterus registry group produced a clinical bilirubin-induced neurological dysfunction (BIND) score to grade the severity and progression of kernicterus. A score of 1 to3 suggests subtle signs of kernicterus in infants with hyperbilirubinaemia (Total serum bilirubinaemia> 95th percentile for age in hours). A score of 4 to 6 suggests moderate ABE which may be reversible with urgent and prompt bilirubin strategies; infants with a failed auditory brainstem response (ABR) screen may have moderate ABE. An infant with a score of 7 to 9 would have advanced ABE. Urgent and prompt intervention to reduce bilirubin levels are recommended to prevent further brain damage , to possibly reverse acute damage and lower the severity of sequelae.4

Clinical signs BIND Score ABE Mental status Normal 0 None Sleepy but arousable; decreased feeding 1 Subtle Lethargy, poor suck and/or irritable/ jittery with strong suck 2 Moderate Semi-coma, apnea, unable to feed, seizures,coma 3 Advanced Muscle tone Normal 0 None Persistent mild to moderate hypotonia 1 Subtle Mild to moderate hypertonia alternating with hypotonia, 2 Moderate beginning arching of the neck and trunk on stimulation Persistantretrocollis and opisthotonos- bicycling or 3 Advanced twitching of hands and feet Cry pattern Normal 0 Normal High-pitched when aroused 1 Subtle Shrill, difficult to console 2 Moderate

Inconsolable crying or cry weak or absent 3 Advanced

Table 1: BIND scores for severity of acute bilirubin encephalopathy in infants with hyperbilirubinaemia.4

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An estimate for the UK incidence of kernicterus is 1 per 100,000 live births.5 This means that for the estimated 669,448 births (in England) per year, there would be around 7 babies that develop kernicterus.2 Criteria 1 met? Met. Kernicterus is rare but the outcomes are severe. Hyperbilirubinaemia is a symptom of various pathologies which are described under Criterion 2. Hyperbilirubinaemia is a condition in itself requiring management and also a risk factor for kernicterus. Kernicterus is a condition which can be fatal or cause severe disability.

2. The epidemiology and natural history of the condition, including development from latent to declared disease, should be adequately understood and there should be a detectable risk factor, disease marker, latent period or early symptomatic stage

Kernicterus is caused by bilirubin toxicity to the brain. Hyperbilirubinaemia has the potential to cause kernicterus, but not all cases with hyperbilirubinaemia will progress to kernicterus. The association between hyperbilirubinaemia and kernicterus has not been fully elucidated. The Newman and Maisels 2006 report said that the risk of kernicterus is extremely low if the serum bilirubin remains below 428 µmol/L in term babies. Since this report the NICE guidelines give a more cautious estimate of risk and says that the factors that influence the risk of kernicterus in babies with hyperbilirubinaemia are  A serum bilirubin level greater than 340 µmol/L in term babies  A rapidly rising bilirubin level of greater than 8.5 µmol/L per hour These estimates were based on six studies (observational and comparative) that had looked at either the association between risk factors and the development of kernicterus or the association between hyperbilirubinaemia and neurodevelopmental outcomes, the clinical manifestations of kernicterus. Three of these studies had evaluated the association of serum bilirubin levels >340 µmol/L with adverse sequelae. Overall the studies were determined to be not of good enough quality to identify risk factors for kernicterus.

Since the publication of the Newman and Maisels report,1 further studies have been published that document the natural history of kernicterus and hyperbilirubinaemia. These include findings of a voluntary USA kernicterus registry, a UK prospective cohort study5 (included also in the NICE neonatal jaundice guideline)2 that followed neonates diagnosed and readmitted with hyperbilirubinaemia and studies from South East Anatolia6 , Denmark7 and China8 . The NICE clinical guideline also reviewed cohort studies that have documented the incidence and natural history across various countries.2

In 1992 the Pilot USA Kernicterus Registry was initiated to identify infants who were ≥ 35 weeks gestational age and who were discharged healthy from their place of birth and went on to have kernicterus.4 As inclusion in this register was voluntary this report cannot be used to infer incidence but details the natural history of kernicterus in infants who were readmitted. The clinical report includes cases who presented between 1992 and 2004 in the USA. National

Page 7 UK NSC External Review guidelines for US clinicians have been in place since 1994 and were updated in 2004.9 The report said that ineffective implementation of the 1994 AAP guidelines are the basis of the continuing reports of kernicterus and suggests that effective implementation of the newly revised 2004 AAP guidelines is a matter of urgent concern.

The US report found that 122 infants who had a gestational age of over 35 weeks were readmitted with documented acute bilirubin encephalopathy of at least moderate severity (see Table 1) or had non-specific acute bilirubin encephalopathy but met criteria for post-iteric or kernicteric sequelae. Most infants had been discharged before 48 hours of age, but about 28% were discharged beyond 48 hours of age. Pre-discharge Transcutaneous bilirubin (TcB) or total serum bilirubin (TSB) levels were measured in only 22 of 125 individuals. Of those whose bilirubin was measured, the severity of hyperbilirubinaemia was unrecognised and even though there was significant hyperbilirubinaemia, follow-up was not considered. Out of 122 infants, 7 were not readmitted, 13 were readmitted on day 2.5-3.5, 24 on day 4, 24 on day 5, 18 on day 6 , 21 on days 7 to 9 and 15 on days 10 to27 . The analysis of registry data supported the consensus opinion that there is no evidence of a specific bilirubin level that is linked to the onset of kernicterus. It shows that although most cases were readmitted to hospital within 9 days after birth there was still a risk of kernicterus in some a month after birth. Similar to the findings of studies assessed in the NICE neonatal jaundice guidelines, disorders which may cause rapid increases in bilirirubin levels such as GP6D deficiency and conditions that lead to haemolysis such as ABO incompatibility and birth trauma (bruising) were found in a high proportion of cases. However, there were a proportion of cases where the underlying pathology was not determined See Figure 1. The pilot USA kernicterus registry also identified two cases of CriglerNajjar syndrome and one case of galactosemia in infants who presented with kernicterus however, these infants were excluded from their analysis as their clinical profiles were considered as usually representing non-preventable causes of jaundice pathology.

Figure 1: Associated pathology of infants who presented with kernicterus in the USA; data from the pilot USA kernicterus registry.4 The number of babies with each of the pathologies is shown.

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A prospective study of severe hyperbilirubinaemia was carried out between 1 May 2003 and May 2005 in the UK and Ireland and was published in 2007.5 This study was supported by the British Paediatric Surveillance Unit and paediatricians were contacted every month and asked whether they had seen any infants “with an unconjugated serum bilirubin concentration of ≥510 µmol/L in the first month of life”. The findings from this study were included in the NICE Neonatal Jaundice guideline. The UK incidence of severe hyperbilirubinaemia (≥510 µmol/L) was estimated at 7.1/100,000 live births (95% CI 5.8 to 8.6). The UK incidence of bilirubin encephalopathy was 0.9/ 100,000 live births (95% CI 0.46 to 1.5). The highest bilirubin level recorded was 802 µmol/L. The mean age of peak serum concentration was 4.3 days (range 1 to 9 days). Twenty cases presented with severe hyperbilirubinaemia in hospital, 84 cases presented on readmission and four were admitted following a home birth. Of the infants who were born in hospital and were readmitted with hyperbilirubinaemia the mean age at initial discharge was 2 days (range 1 to 5 days).

Of the 14 infants who had bilirubin encephalopathy, two infants presented whilst still in hospital, nine were readmitted and 3 had been born at home. The infants who had bilirubin encephalopathy had significantly higher peak serum bilirubin concentrations than jaundiced infants without encephalopathy (mean 627 µmol/L versus 573 µmol/L, p=0.037). The infants with encephalopathy were more likely to be boys (12 (85%), p=0.37); more likely to be black or British black (6 ,43%), p<0.001; were more likely to have a coexisting infection (3 ,21%), p=0.007) and were more likely to be treated with an exchange transfusion (10 ,66% versus 38,40%). The study authors performed a multiple logistic regression model and demonstrated that ethnic group (black) (odds ratio 19.0, 95% CI 2.5 to 144.7) and glucose 6-phosphate dehydrogenase deficiency (odds ratio 28.2, 95% CI 2.6 to 307.7) independently increased risk of encephalopathy in infants with hyperbilirubinaemia. In their discussion the researchers suggested that infants of ethnic minorities may be vulnerable for two reasons. Firstly, the evaluation of the severity of jaundice may be difficult and secondly there may be a higher prevalence in haemolytic diseases such as G6PD in some ethnic minority groups.

Four infants who developed kernicterus had the associated pathology of blood group incompatability (one had rhesis incompatability and three had ABO incompatability), 3 infants had G6PD deficiency, 2 infants had an infection, 1 infant had no identified cause (See Figure 2). At 12 months three of the infants had died, three of the infants had normal neurological function, six had neurological impairment and two were lost to follow up. There are currently no mandatory reporting systems available for hyperbilirubinaemia. As cases of kerniterus have been observed with serum bilirubin levels below 510 µmol/L, follow up of all cases of jaundice rather than just severe cases may be necessary to quantify the extent of the problem.

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Figure 2: The proportion of cases showing associated pathology with hyperbilirubinaemia (above 510 µmol/L) and kernicterus in a UK and Ireland cohort. In total there 108 cases who meet the criteria for hyperbilirubinaemia and there were 14 cases of kernicterus between 2003 and 2005. A Danish population based cohort study published in 2009 found an incidence of kernicterus in Denmark of 1.3/100,000 live births. Kernicterus was considered present if all three of the following criteria were observed i) the child had been exposed to potentially toxic levels of serum bilirubin, using a 450µmol/L TSB inclusion cut-off for cases (this level is based on the cut- off for exchange transfusion in Denmark), ii) presentation with clinical symptoms and signs identical to the intermediate or advanced phases of kernicterus in the neonatal period, iii) developed impairments (e.g. neurological or motor impairments) or death as a potential consequence of high serum bilirubin. The focus of the study was to look at obstetric outcomes of Danish children with a diagnosis of kernicterus. The study had analysed the pregnancy and delivery records for these infants and identified no particular potential risk factors throughout the pregnancy or delivery associated with a subsequent risk for development or predevelopment of kernicterus. Mental retardation occurred in 5/9 children, hearing impairment and cerebral palsy both occurred in 4/9 children and three children died before two years.7

A cohort study carried out in South East Anatolia followed 56 male neonates who needed an exchange transfusion due to hyperbilirubinaemia. The cut-offs for exchange transfusion was a serum bilirubin concentration of over 342 µmol/L at 24 to 48 hours after birth and over 428 µmol/L after 48 hours. Ten (18%) of the neonates had G6PD deficiency , the mean bilirubin concentration of this subgroup was 720 µmol/L ±234 µmol/L and five of the ten infants developed kernicterus. In the 46 infants, requiring exchange transfusion but who did not have G6PD deficiency the mean concentration was 544µmol/litre ±133 µmol/L. Out of this group, four developed kernicterus. The mean age at time to readmission was 3.4 days ± 1 day for infants with G6PD deficiency and 5.1 ± 2.9 days for infants without G6PD deficiency.6

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A retrospective study analysed a cohort of 413 Chinese infants with peak serum total serum bilirubin values over 342 µmol/L. This study excluded pre-term babies under 34 weeks and babies with a birthweight under 2,000 grams or those who had a G6PD deficiency. Twenty one per cent had blood group incompatability (predominantly ABO incompatability), the outcomes of these infants was compared to infants who had hyperilirubinaemia of unknown aetiology (except breast milk feeding). A higher proportion of neonates with blood group incompatabilities were likely to have a peak TSB before they were three days old (33%)compared to the non-blood group incompatability group (1.8%). They also tended to be more likely to have a low haemoglobin level and reticulocyte count indicating that they were more likely to develop early-onset, hemolysis-mediated hyperilirubinemia. Four infants with blood group incompatabilities developed kernicterus. Two of these infants were Rh incompatable, their peak serum bilirubin levels occured at days 1 (522 µmol/L) and 2 (479 µmol/L) after birth. Two of the infants were ABO incompatable, their peak TSB levels were at days 7 and 5 and were 660µmol/L and 357 µmol/L.8

The NICE guidelines assessed 10 cohort studies that had documented cases of kernicterus (or bilirubin encephalopathy) from eight countries, and noted that a high proportion of these cases had blood group incompatabilty, G6PD deficiency or infection. However, across these cohorts between 7 and 43% were idiopathic or of no known cause.

The newer publications which have described pathologies found in a high proportion of kernicterus cases do not provide alternative potential targets for which to screen owing largely to their high prevalence in the UK population with only a small proportion of babies born with each pathology that causes hyperbilirubinaemia subsequently developing kernicterus. G6PD deficiencies are relatively common, with a UK prevalence of 1 in 5 in some ethnic groups. The severity of symptoms of G6PD deficiency is variable but most people with G6PD deficiency have completely normal health.10 Blood group incompatabilities are potentially quite common, for example it is estimated that 15% of women are Rhesus D negative, however primary prevention strategies may lower the number of cases of jaundice resulting from blood group incompatabities (see Section 3). The rate of serious acute infections has been estimated as 2 in 1,000 live births with the incidence rising in small babies.11The prevalence of Gilbert syndrome, a benign but chronic periodic jaundice, is estimated by the British Liver Trust to have a UK prevalence of 4%.12CriglarNajjar syndrome has an incidence of around 1 per million live births. Infants with this condition require on-going treatment.13

In summary, cases of kernicterus have been observed in the first month of life but the majority occur within the first week of life. G6PD deficiency, blood group incompatability (haemolysis) or infection are common background pathologies in documented cases of kernicterus which tend to lead to an accumulation of bilirubin within this first week.

Should a screening programme be introduced, it may need to be addressed whether different management and treatment cut-offs for term compared to preterm babies are required. A study compared the outcomes of preterm and term neonates with a peak total serum bilirubin (TSB) of over 400 µmol/L and/or signs of bilirubin encephalopathy. Two of the infants were under 31

Page 11 UK NSC External Review weeks gestational age, four were 34 to 38 weeks gestational age and five were 37 to 40 weeks gestational age. The range of serum TSB levels were 235 to 583 µmol/L in the preterms and 423 to 720 µmol/L in the term babies. The study concluded that cerebral palsy occurred at relatively low TSB levels in preterms but only at high levels in full terms.14

Kernicterus is caused by bilirubin toxicity however the association between hyperbilirubinaemia and the progression to kernicterus has not been fully elucidated. There are several pathologies that are associated with rapid rises in bilirubin levels, but a proportion of kernicterus cases are idiopathic. Criteria 2 met? Not met. The epidemiology of kernicterus has been described for the UK following a recent prospective study of cases of severe hyperbilirubinaemia in the UK. However, there still remains uncertainty about the natural history of kernicterus. The complexity of the natural history is compounded by the rarity of kernicterus and this makes it difficult to draw conclusions about the progression from jaundice to significant hyperbilirubinaemia to kernicterus. Particularly there is no identified serum bilirubin level which accurately predicts progression to kernicterus.

3. All the cost-effective primary prevention interventions should have been implemented as far as practicable Since the last policy review the NICE technology appraisal (TA 156) Routine antenatal anti-D prophylaxis for women who are rhesus D negative has been published. The recommendations say “Routine antenatal anti-D prophylaxis (RAADP) is recommended as a treatment option for all pregnant women who are rhesus D negative (RhD) negative and who are not known to be sensitised to the RhD antigen”.

There are NICE guidelines on management of early onset neonatal infections in development.

Breast feeding has been shown to be a risk factor for significant hyperbilirubinaemia, but the reasons for this are not yet clear. We were unable to identify articles from the updated search that had assessed modifications to breastfeeding for prevention of hyperbilirubinaemia. Breastfeeding is encouraged owing to multiple health benefits and there is no recommendation that breastfeeding should be interrupted if jaundice develops. Furthermore during phototherapy it is not recommended that breastfeeding be interrupted, and maternal expressed milk is the additional feed of choice, if available, for babies undergoing phototherapy.2

Screening for rhesus negative women has been implemented. Criteria 3 met? Partly met. Preventative treatments are available for some causes of hyperbilirubinaemia, but not all have been implemented.

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4. If the carriers of a mutation are identified as a result of screening the natural history of people with this status should be understood, including the psychological implications. There are no updates to the Newman and Maisels report which says: While screening for hyperbilirubinaemia does not itself identify carriers of a mutation, it might identify people in whom additional testing for G6PD deficiency (or possibly other mutations) would be indicated. NICE recommends a follow up GP6D test if a neonate has hyperbilirubinaemia taking into account ethnic origin.2 People who are diagnosed with G6PD deficiency through a blood test measuring the amount of the enzyme may receive advice on medicines and foods to avoid if possible and to look for symptoms of hemolysis or anaemia. The natural history of G6PD, but not the psychological implications are understood. Criteria 4 met? Not applicable

5. There should be a simple, safe, precise and validated screening test The Newman and Maisels report addressed the use of visual inspection for jaundice, transcutaneous bilirubin measurements and serum bilirubin measurements to screen for hyperbilirubinaemia. Since that report NICE has systematically reviewed the evidence for these methods to assess jaundice or measure bilirubin. In particular, the guidelines reviewed and assessed the accuracy of transcutaneous bilirubin measurements against the gold standard of serum bilirubin measurement. As hyperbilirubinaemia causes kernicterus, measuring bilirubin levels may provide an appropriate marker for risk of developing kernicterus, however, without further understanding of the relationship between bilirubin level and kernicterus the tests described below may not be appropriate for use as a whole population screening test We have considered the evidence for the accuracy of tests that could be used in two potential screening strategies for kernicterus. The first is a one-step test where all babies have their bilirubin level measured. The second is a strategy where bilirubin is measured following visual inspection for presence or absence of jaundice.

Transcutaneous and serum bilirubin measurements Serum bilirubin measurements are the gold-standard method to measure bilirubin but the 2006 report by Newman and Maisels highlighted that there is significant intra-laboratory variability in total serum bilirubin measurements, with coefficients of variation across laboratories 10-15% being reported. At the time of the Newman and Maisels report the authors highlighted developments in using a more appropriate standard which showed promise in reducing this variability. The updated search identified no journal articles that had addressed this issue directly. Potential problems with using serum bilirubin measurements in a screening program would be that repeated blood sampling may not be appropriate (unless bilirubin serum measurements could be performed on a blood sample taken for routine screening) and parents may find it unacceptable for unnecessary blood tests to be performed if their child has no visible sign of jaundice (See Section 7).

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Studies, reported below, have assessed whether transcutaneous measurement of bilirubin correlates with serum measurements; can predict the likelihood of severe hyperbilirubinaemia; or could reduce the need for blood tests in lower risk babies. Transcutaneous bilirubin measurements would have the advantage as a screening test as the test itself is non–invasive and may be preferred by parents to a blood test.

Available devices on the market include BiliChek, the Minolta JM-103 (the Minolta JM-102 is no longer available from the manufacturers) and Bilimed. The NICE guidelines appraised evidence for the accuracy of transcutaneous bilirubin measurements compared with total serum bilirubin measurements in order to determine when transcutaneous measurements could be used and when a confirmatory measurement of serum bilirubin should be made.2

JM103: The correlation coefficients between the transcutaneous bilirubin readings and serum bilirubin levels were found to range from a moderate positive 0.77 to a significantly positive 0.93. In term babies, three out of four studies found an underestimation of serum bilirubin levels (by a mean of 12 to 27 µmol/L). One study found an overestimation of bilirubin by ≥51 µmol/L in 17.4% of black babies, 2.0% of white babies and 3.3% of other babies. In pre-term babies the correlation was positive with values of 0.79 to 0.92 but the JM-103 consistently underestimated bilirubin levels by an average of 19 ± 32µmol/L). It was noted that the three studies assessing JM 103 that were meta-analysed were highly heterogeneous.

BiliChek: The correlation coefficient with serum bilirubin ranged from 0.80 to 0.87. BiliChek was a less accurate measure compared to serum bilirubin at bilirubin levels > 250 µmol/L. In one study on African babies, BiliChek readings “showed a reasonable correlation with serum bilirubin values but the difference between transcutaneous bilirubin and serum bilirubin was greatest in babies with darker skin tones”.

Precise measurements are particularly vital if a baby has jaundice in the first 24 hours as the cut- off margins for different treatments are narrower. For example a 6 hour old baby with bilirubin levels > 125 µmol/L would be indicated to start phototherapy whereas a baby with bilirubin levels > 150 µmol/L would be indicated for exchange transfusion according to the NICE guidelines. A 24 hour old baby would start phototherapy if their bilirubin levels were above 200 µmol/L or would start exchange transfusions if their bilirubin levels were above 300 µmol/L.

The overall recommendations from NICE based on these findings is that transcutaneous bilirubinometers may be used in babies with a gestational age of 35 weeks or more and a post natal age of more than 24 hours (a serum bilirubin measurement may be used in the absence of a transcutaneous bilirubinometer). However, if the transcutaneous bilirubin measurement is above 250 µmol/L the measure should be repeated using a blood sample. Transcutaneous bilirubin measurement is not recommended to assess bilirubin levels in the first 24 hours of life. Publications retrieved from the updated search that were not included in the NICE guideline generally concur with the NICE appraisal.

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Bilimed One publication assessed a different device Bilimed. The conclusions were that the limits of the agreement between the device and serum measurements were too wide to be acceptable in the clinical setting (the mean deviation was approximately – 14 µmol/L for term neonates and + 16 µmol/L for preterm neonates. There was also a trend towards poorer correlation with increasing bilirubin levels.15

Lower reliability with transcutaneous measurement is found in preterm babies, but measurements over the sternum or abdomen, rather than the forehead, can narrow the difference between transcutaneous bilirubin measurements and serum bilirubin. However, over a certain bilirubin concentration transcutaneous bilirubin measurements may over- or under- estimate bilirubin levels to such an extent that transcutaneous bilirubin measurements should not be used. These studies suggested that over a cut-off of 239 to 250µmol/L, serum bilirubin measurements should be used.16-23

Screening asymptomatic neonates using transcutaneous bilirubin measurement is one option and in comparison to screening with serum bilirubin may be a simpler and less invasive procedure. If positive, follow up serum bilirubin measurements would be required in some cases.

Visual inspection for jaundice

The NICE guideline recommends that all neonates should have a visual inspection for jaundice within the first 24 hours after birth and that bilirubin should be measured in neonates that are visibly jaundiced. These guidelines suggest that in babies with light skin tones jaundice is usually visible at levels of bilirubin > 90 µmol/L.2

The NICE guideline addressed the problem of recognition of jaundice by visual inspection. The guideline said that across these studies clinical examination of jaundice had a poor diagnostic accuracy (i.e. could not determine jaundice where the underlying bilirubin levels were of clinical significance). However, visual inspection for absence of jaundice did have a high negative predictive value (NPV) for ruling out the presence of severe hyperbilirubinaemia (i.e. if the baby did not have visual signs of jaundice, there was a high probability that they would not have hyperbilirubinaemia). Three studies have assessed the NPV in the absence of jaundice in healthy full-term babies and defined severe hyperbilirubinaemia as greater than the 40th centile on Bhutani’s nomogram (see Section 6), or serum bilirubin levels > 250 µmol/L. The timing of the assessment was at a median of 55 hours (range 9 to 252 hours) in one study, 2 days (range 8 hours to 7 days) in another and not described in the third. The NPV in absence of jaundice ranged from 91.9% to 100% while the calculated negative likelihood ratio ranged from 0.45 to 0.15.

Evidence was not presented for whether skin colour affected the NPV of the absence of jaundice in the NICE neonatal jaundice guideline. Since the publication of this guideline we found one

Page 15 UK NSC External Review study that supports the evidence presented in the NICE guideline, showing that the visually determined extent of jaundice could not predict the development of severe hyperbilirubinaemia.24

The majority of studies reviewed by NICE measured the reliability of clinical staff to determine the severity of jaundice. Reliability of clinical staff to visually discriminate presence of jaundice from absence of jaundice was appraised by a US study which was cited by NICE.25 It found that agreement between observers regarding the presence of jaundice at various body sites was poor (0- 23% agreement beyond chance: best agreement when the location at which the jaundice was assessed was between the nipple line and the navel) but that the correlation between estimated and actual bilirubin values was slightly better (Pearsons correlation coefficient, 0.43 to 0.54 (a value of 1 would mean perfect correlation and a value of 0 would mean no correlation)) . A study cited by the NICE guidelines2,26 found there was only moderate agreement between physicians, nurses and parents as to whether an infant was jaundiced or not (κ ~0.48), the babies’ bilirubin levels ranged from 27.4 µmol/L to 316.4 µmol/L but all babies with bilirubin levels over 205 µmol/L (the AAP cut-off for phototherapy for infants 25 to 48 hours old) were correctly identified as jaundiced by parents, nurses and physicians. No studies reported whether TcB could detect presence/absence of jaundice (using a defined cut-off) better than visual inspection.

The issue for screening is how transcutaneous or serum bilirubin measurement compare for diagnostic accuracy with a policy of waiting for the first sign of jaundice and then performing a diagnostic, rather than screening, bilirubin measurement with either method. The update search identified no new studies that improved on the previous estimate of a high NPV (range 91.9% to 100%) for the absence of clinical jaundice based on visual inspection in ruling out important hyperbilirubinaemia. The utility of testing asymptomatic neonates is covered in other sections. Criteria 5 met? Met; simple tests for measuring bilirubin levels with reasonable diagnostic accuracy are available.

6. The distribution of test values in the target population should be known and a suitable cut-off level defined and agreed

The relationship between bilirubin level and kernicterus remains uncertain and it is unclear which additional factors besides high bilirubin levels may be needed for a neonate to develop kernicterus. Treatment algorithms have been produced which identify levels of bilirubin by age which require treatment. If the goal of screening is to identify newborns in need of immediate treatment to lower bilirubin levels then it is likely that the treatment guideline suggested by NICE could achieve this. The NICE guideline provides the bilirubin level by age for which infants should be monitored, receive phototherapy or receive exchange transfusion. These treatment cut-offs are largely based on consensus rather than on an evidence base and are discussed in section 10 and 11.

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If the goal of screening is risk assessment, including neonates that do not require immediate treatment; knowledge on distribution of bilirubin levels in newborns and clinical risk factors for subsequent development of kernicterus are needed. In this section we have appraised the accuracy of risk prediction models to predict the risk of development of severe hyperbilirubinaemia and the extent to which these risk models are generalizable to the UK population.

Two main approaches have been used to predict risk. The first is to use pre-discharge bilirubin levels to assess the risk of a rise in bilirubin to a clinically significant level using a nomogram. The second is to conduct a risk assessment using a clinical risk factor score. We have considered the NICE appraisal of pre-discharge risk assessment tools, including risk nomograms based on serum bilirubin measurements, risk nomograms based on transcutaneous bilirubin measurements and combination risk assessment tools which combine risk bilirubin nomograms with a risk score to address whether there is an agreed risk assessment tool to determine whether it is safe to discharge neonates. We have additionally included studies published since the NICE systematic search.

Bilirubin levels in the first 24 hours The NICE guideline analysed four studies that had assessed whether measuring serum bilirubin levels in the first 24 hours of life predicted hyperbilirubinaemia (≥ 290µmol/L) at days 3 to 5. The studies were carried out in Spain, India, Turkey and Isreal. The conclusions drawn were that serum bilirubin > 102 µmol/L within the first 24 hours of life is predictive of serum bilirubin > 290 µmol/L between days 3 and 5. These studies used measurements of bilirubin taken at one point on the first day of life, and does not take into account that bilirubin levels will naturally rise over the first few days of life. Bilirubin nomograms Other approaches have used age-dependent bilirubin levels to determine risk. The NICE appraisal described two published studies describing nomograms to predict risk of subsequent hyperbilirubinaemia using pre-discharge bilirubin measurements. These studies were published prior to 2005. The larger of the two, produced the Bhutani nomogram, which plotted the distribution of pre- and post-discharge bilirubin by age in a cohort of 2,840 American babies. The nomogram defined a significant bilirubin level as above the 95thcentile, the clinical significance for choosing this cut off was not described, however the bilirubin levels of infants above this centile were described to indicate “close supervision, possible further evaluation, and sometimes intervention if brain damage is to be prevented”. The 95th centile cut-off at 24 hours was ≥ 137 µmol/L, ≥239 µmol/L at about 48 hours and ≥ 290 µmol/L at around 84 hours of age. The NICE guideline consideration of this study also highlighted that The universal application of an hour-specific bilirubin estimation could not be relied on as data were lacking for babies in the first 24 hours of life and also for those with jaundice due to haemolytic disease of the newborn. The Bhutani nomogram excluded data from neonates who had neonatal illness or had a positive Coombs test and a known increased risk of subsequent hyperbilirubinaemia secondary to ABO

Page 17 UK NSC External Review and Rh incompatibility pre-discharge. G6PD screening was not performed. After the initial analysis, newborns that required phototherapy before age 60 hours to control unexplained rapidly rising TSB levels were excluded from the predictive nomogram. Newman and Maisels reported that this nomogram had been shown to be a good predictor of risk or significantly increasing TSB levels, but they said The percentile labels on this nomogram are not valid even in the populations from which they were derived and may be far from the mark in other populations The Bhutani nomogram has been utilised by the American Academy of Pediatrics as a tool for determining risk as part of its management algorithm in their guidelines for neonatal jaundice and even though it is not new since the last policy review it has been referred to, and used by some of the newly published studies therefore we considered it appropriate to describe in greater detail.

The Bhutani nomogram determined the ability of a pre-discharge TSB level to predict significant hyperbilirubinaemia defined as a subsequent TSB value in the high-risk zone ( ≥95th percentile of TSB values regardless of age). For each pre-discharge TSB they looked at the binary outcome; whether subsequent hyperbilirubinaemia was present or not present. They then calculated how well a pre-discharge TSB above the 95th percentile, above the 75th percentile or above the 40th percentile predicted presence or absence of subsequent hyperbilirubinaemia. For neonates who had pre-discharge TSB level below the 40th percentile, 100% had subsequent TSB below the 40th percentile. The sensitivity of this nomogram using the 95th percentile demarcator for predicting risk for hyperbilirubinaemia was 54% and the sensitivity was 96.2%.However, the positive predictive value was low (39.5%). In a screening programme this may lead to unnecessary follow up in a high proportion of neonates. Presumably if nomograms such as this one were used to assess pre-discharge risk of subsequent kernicterus the predictive value would be significantly lower.

≥95th centile cut-off ≥75th centile cut-off ≥40th centile cut off subsequent 68 114 126 hyperbilirubinaemia present (n) Subsequent 104 414 958 hyperbilirubinaemia absent (n) Sensitivity % 54% 90.5% 100% Specificity % 96.2% 84.7% 64.7% Positive likelihood ratio 14.1 5.9 2.8 Negative likelihood ratio 0.478 0.112 0 Positive predictive value % 39.5% 21.6% 11.6% Negative predictive value % 97.8% 99.5% 100% Table 2: The predictive ability of the Bhutani nomogram.27

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Application of transcutaneous bilirubin measurements to a bilirubin nomogram For a screening programme transcutaneous bilirubin measurements are likely to be more accepted as a pre-discharge measure for risk prediction than serum bilirubin measurements. Subsequent studies to Bhutani et al., 1999 have compared the predictive ability of nomograms generated using serum bilirubin measurements or transcutaneous bilirubin measurements of cohorts. NICE reviewed one study that had compared TcB to TSB for prediction of hyperbilirubinaemia in a multiracial population by plotting both serum and TcB measurements on the Bhutani nomogram. This American cohort study of 490 babies found that TcB measurements over the 75th centile measured at 24 to 72 hours of age predicted hyperbilirubinaemia with a sensitivity of100%, a specificity of 88% and a likelihood ratio for a positive result of 8.4. None of the babies with a serum bilirubin level in the high risk zone had a transcutaneous bilirubin recording below the 75th centile on the Bhutani nomogram. Since the publication of the NICE guidance the distribution of TcB values in various cohorts has been assessed.28,29The inclusion and exclusion criteria of the cohorts on which these were constructed differ. This means that their generalizability to a whole population may be limited.

Definition of demarcators for pre-discharge risk zones The Bhutani nomogram classified clinically significant hyperbilirubinaemia as age specific TSB levels over the 95th percentile. However, this may not reflect the treatment cut-offs recommended in the NICE guideline. The Bhutani nomogram used centiles of the pre-discharge TSB distribution to demarcate pre-discharge risk zones; however subsequent studies have used other approaches. A study in a Greek cohort of 2,039 neonates determined the predictive ability of pre-discharge TcB measurements for significant hyperbilirubinaemia (defined as any TSB level that exceeded the hour specific threshold value for phototherapy according to the guide-lines presented by the AAP).30In this study all newborns whose mothers were known to be Rh factor negative or who had positive indirect Coombs tests, had their blood group evaluated and a direct Coombs test performed. Additionally newborns who required phototherapy had their blood group evaluated, a direct Coombs test and were assessed for glucose-6-phosphate dehydrogenase deficiency. The study excluded neonates that had been admitted to the intensive care unit, neonates with positive direct Coombs test results, neonates with jaundice requiring intervention in the first 24 hours and G6PD deficiency. The TcB was measured at 12, 18, 24, 36, 48, 60 and 72 hours and the final measurement was between 96 and 120 hours. TcB measurements were followed immediately by TSB levels if the TcB level was over 256.5 µmol/L or was less than this value but within 34 µmol/L of the AAP phototherapy threshold. The TcB risk levels for subsequent hyperbilirubinaemia were determined using positive and negative likelihood ratios instead of TcB percentiles as in the Bhutani nomogram. Likelihood ratios were used as they are not affected by the prevalence of hyperbilirubinaemia and were considered by the researchers to provide more reliable estimations of hyperbilirubinaemia even amongst heterogeneous populations. The likelihood ratios were calculated using ROC curve analysis. TcB levels with a positive LR of > 10 was considered to denote that bilirubin levels would increase to subsequent hyperbilirubinaemia requiring treatment. TcB levels with a negative LR of <0.1 were considered to have a decreased risk of subsequent hyperbilirubinaemia. The high risk zone was designated as TcB measurements which had a positive LR of > 10. The low risk zone were TcB measurements with a negative likelihood ratio of less than 0.1. A third demarcator for “minimal risk” was defined as TcB levels with a negative LR of 0. The area under the curve (AUC) was 0.908 at 24 hours and increased in predictive value with increasing time, for example at 48

Page 19 UK NSC External Review hours the AUC was 0.961. The study found that at 24 hours their high risk demarcator coincided with the 95th percentile of the Bhutani nomogram. However, at 48 hours it approached the 75th percentile which on the Bhutani nomogram would mark intermediate risk. This study and the studies described above suggest that pre-discharge TcB measurements may be appropriate to use instead of TSB measurements.

Above high risk Above low risk Above minimal risk demarcator demarcator demarcator (above 136.8 µmol/L at (above 99.2 µmol/L at (above 90.6 24 hr) 24 hr) µmol/L at 24 hr) Subsequent significant 65 86 88 hyperbilirubinaemia present Subsequent significant 81 605 636 hyperbilirubinaemia absent Sensitivity 73.9% 97.7% 100% Specificity 93.9% 54.2% 51.9% Positive likelihood ratio 12.1 2.1 2.1 Negative likelihood ratio 0.28 0.04 0 Positive predictive value 44.5% 12.4% 12.2% Negative predictive value. 98.2% 99.7% 100% Table 3: The predictive ability of the Varvarigouet al. nomogram at 24 hours30

Rate of rise of bilirubinnomogram A systematic review published in 2009 (not included in the NICE guidelines) which compared available nomograms in the literature defining trends in TcB levels across populations with different risk factor profiles. The review also presented a mathematical bilirubin kinetics model describing the natural course of jaundice and the rate of rise needed to cross percentile curves. Measuring the rate of rise requires multiple measurements, in a screening programme the rate of rise in bilirubin may be important for neonates that do not require initial treatment, but may be at risk of requiring subsequent treatment and require monitoring.

The review assessed four TcB nomograms (published between March 1999 and March 2009), three of which had been constructed for cohorts of over 2000 infants, one for a cohort of 284 infants. One nomogram was constructed in a European population of white race/ethnicity babies, one was constructed in a Hispanic and one in a Thai neonate population, the fourth nomogram comprised of North American neonates (approximately 73% white, 10% black and equal percentages of other races). Some jaundice risk factors differed across these populations or were not reported, such as G6PD deficiency.

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The review found that significant differences in bilirubin values exist across populations. The systematic review assessed at what age the bilirubin levels began to plateau (saying the plateau point can be conceptualised as the postnatal age when rates of bilirubin production and excretion are equal). It found that the Thai neonates tended to reach this at approximately 72 hours of life, the neonates of the two predominantly white populations reached this plateau between 73 and 96 hours of life, whereas the Hispanic population reached this at 96 hours.

As bilirubin levels plateau the rate of bilirubin rise should decrease over time. The study calculated the exaggerated rate of rise (EROR) need to cross the percentile curves for each cohort nomogram, from the 25th to 50th percentiles and from the 50th to the 75th percentiles over four epochs (12-24 hours, 24 to 48 hours, 59 to 72 and 73 to 96 hours of life). The review found that there were differences in the rate of rise needed to cross percentile curves between the cohorts. The researchers found that the rate of rise needed to cross percentile curves was approximately 1.9 µmol/L/hr for the first 48 hours, which was lower than previously thought. The AAP has suggested that a rate of rise of 4.3 µmol/L/hr should raise concern. NICE states a rate of rise of 8.5 µmol/L per hour in the first 24 hours influences the risk of kernicterus. However, the evidence was limited to support this estimate.2 A study in an Indian cohort published in 2009, assessed the predictive ability of a TcB measurement taken at 24 ± 6 hours compared to a TcB measurement taken over 12 hours later but within 48 hours to predict subsequent hyperbilirubinaemia in 348 neonates. The study also assessed the predictive ability of rate of increase of bilirubin between these two time points by reporting the ROC area under the curve. The ROC area under the curve value was 0.77 for the 24 hour TcB measurement, 0.87 for the second TcB measurement and 0.86 for the rate of bilirubin level change. The researchers concluded that changes in TcB levels do not offer any additional clinical benefit to a TcB measurement at 30 to 48 hours.2,31

Clinical risk scores The NICE guideline also appraised studies in which risk scores had been used to predict post- discharge risk of hyperbilirubinaemia. One nested case control study (cases73newborns with peak total serum bilirubin levels ≥428 µmol/L, and 423 controls randomly selected from a cohort of 61 387 babies with a birthweight≥ 2000g and gestational age ≥ 36 weeks and a maximum serum bilirubin level below 428 µmol/L) assessed early jaundice, gestational age per week, breast feeding at discharge, Asian race, bruising, cephalhematoma and maternal age to develop a risk model score for developing hyperbilirubinaemia after discharge. The risk index was developed by assigning points to the risk factors which were approximately the same as the odds ratios for these factors determined with multiple regression analysis.. The researchers determined that if a threshold was set at more than 10 points on this risk index then the positive likelihood ratio of babies having serum bilirubin levels ≥ 428 µmol/L was 2.2. If a score of more than 20 points was used as a threshold, the positive likelihood ratio was 18.2. The discrimination of the risk index to predict hyperbilirubinaemia (≥ 428 µmol) compared to normal levels was good (c=0.85). A subsequent study, described in the NICE systematic review, found that a partial risk index score combined with pre-discharge serum bilirubin hour specific scores improved the predictive ability of risk scores alone to predict a subsequent hyperbilirubinaemia of ≥ 342 µmol/L (partial risk index score alone c=0.69, combined pre-discharge bilirubin with partial risk score c=0.86).

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A North American prospective cohort study of 823 neonates was described in the NICE guidelines that looked at the ability of TcB measurements and/or clinical risk factors obtained before 52 hours of age to predict significant hyperbilirubinaemia (a TcB or TSB measured bilirubin level that, at any time after birth, exceeded or was within 17 µmol/L of the hour specific phototherapy treatment threshold recommended in the AAP’s clinical practice guideline on the management of neonatal hyperbilirubinaemia) between days 3 to 5. The researchers produced three logistic regression models to predict the outcome of significant hyperbilirubinaemia: (1) a model that included pre-discharge bilirubin risk zone alone; (2) a model that included clinical risk factors other than pre-discharge bilirubin risk zone and (3) a model that combined both.

The predictive accuracy performance of the combination model (bilirubin risk zone plus gestational age (GA) and percentage weight loss per day) (c statistic = 0.96; 95% CI: 0.93 to 0.98) was better than bilirubin risk zone alone (c= 0.88) or a clinical risk factor model (GA, method of feeding, black race, extent of jaundice and gender). For children with pre-discharge bilirubin in the high-intermediate or high risk category a gestational age of less than 38 weeks increases the risk of significant hyperbilirubinaemia several fold.32 A combination of bilirubin risk zone with gestational age was also found to be better in predicting subsequent hyperbilirubinaemia than pre-discharge bilirubin alone in a follow up Portuguese cohort of 463 neonates.33

Clinical risk factors recommended to be assessed by NICE The NICE Guidelines Development Group considered, based on the evidence presented in the above studies, that assessment of risk factors was important. The recommendations were that parents and carers should be made aware of these risk factors and that those responsible for the care of newborn babies should take them into account when examining the baby and deciding on management options. The NICE recommendations are that if the baby does not have visible jaundice in the first 24 hours, but has the risk factors:  Gestational age under 38 weeks  A previous sibling with neonatal jaundice requiring phototherapy  Mother’s intention to breast feed exclusively Then they should receive an additional visual inspection by a healthcare professional within 48 hours. Summary Risk models to predict subsequent hyperbilirubinaemia have been developed. Initially nomograms were produced to predict risk of hyperbilirubinaemia, following assessment of cohort bilirubin levels measured using a blood test. Subsequently similar models have been produced using transcutaneous bilirubin measures, which if screening were introduced would be likely to be the more acceptable measurement method. However, the testing of the accuracy of these models has used different definitions of hyperbilirubinaemia. Some models used cut- offs for treatment as the definition but cut-off bilirubin levels for treatment of hyperbilirubinaemia have been reached by a consensus (as discussed in section 10). Additionally

Page 22 UK NSC External Review these models have not been assessed for their predictive ability for kernicterus and the level of accuracy with which they would identify a population at increased risk of kernicterus is uncertain.

It is not known how well risk assessment models apply to a UK population. Owing to the differences in how bilirubin was measured and in the inclusion criteria of cohort studies, a meta- analysis of data from various studies may provide a more generalizable distribution on which to base risk estimates. The NICE guidelines do not currently recommend the use of an hour specific bilirubin nomogram such as the Bhutani nomogram owing to a lack of data for the first 24 hours and being based on a non-comprehensive population making them unreliable for universal application.

Studies have shown that combining clinical risk factor data with bilirubin levels could potentially improve risk assessment tools. TcB measurements are likely to be the most acceptable test pre- discharge. A combination of TcB with follow up TSB if TcB is over a certain threshold may allow valid TcB nomograms to be produced. In the US the AAP guidelines recommend a pre-discharge measurement of bilirubin level using TSB or TcB and/or assessment of clinical risk factors. However in the UK the current management recommendations are that all babies should be assessed visually for jaundice in the first 24 hours with a further assessment within 48 hours only for infants with clinical risk factors for jaundice. Criteria 6 met? Not met, cut off levels for risk prediction of kernicterus are not agreed and the natural history not adequately understood to allow determination of a meaningful cut-off.

7. The test should be acceptable to the population The updated search identified no recent research on acceptability of the two approaches to measure bilirubin levels: a blood sample or a transcutaneous bilirubin measurement using a small hand held device with a possible follow up blood test. A heel stick test for total serum bilirubin requires 50 µL of blood, whereas laboratory studies may require 1mL of venous blood.30 As highlighted in the Newman and Maisels report, transcutaneous measurement is quick and painless. It is unlikely that such a test would be unacceptable to the public.

Criteria 7 met? Not clear, there were no studies identified in the updated search which assessed acceptability of bilirubin measurements.

8. There should be an agreed policy on the further diagnostic investigation of individuals with a positive test result and on the choices available to those individuals The NICE guidance recommends that in addition to a full clinical examination by a suitably trained healthcare professional, clinicians should carry out all of the following tests in babies with significant hyperbilirubinaemia as part of an assessment for underlying disease.  Serum bilirubin (for baseline level to assess response to treatment)  Blood packed cell volume

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 Blood group (mother and baby)  DAT (Coombs’ test). Interpret the result taking into account of the strength of reaction, and whether mother received prophylactic anti D immunoglobulin during pregnancy. When assessing the baby for underlying disease consider whether the following tests are clinically indicated.  Full blood count and examination of blood film  Blood glucose-6 phosphate dehydrogenase levels taking into account of ethnic origin  Microbiological cultures of blood urine and/ or cerebrospinal fluid (if infection is suspected) Criteria 8 met? Met. There is an agreed policy on further follow up of neonates with a test result positive for hyperbilirubinaemia to identify potential pathological causes of the jaundice.

9. If the test is for mutations the criteria used to select the subset of mutations to be covered by screening, if all possible mutations are not being tested, should be clearly set out Criteria 9 met? Not applicable

10. There should be an effective treatment or intervention for patients identified through early detection, with evidence of early treatment leading to better outcomes than late treatment

Early detection for kernicterus involves detecting high bilirubin levels prior to the occurrence of bilirubin induced neurotoxicity. In this section we have appraised the evidence for bilirubin lowering treatments. Evidence for bilirubin-lowering treatment strategies affecting the incidence of kernicterus is discussed in section 13.

The guideline development group which determined bilirubin levels at which therapy was indicated said there is: No reliable evidence to inform the choice of thresholds for commencing therapy- including phototherapy and exchange transfusion- in babies with jaundice. This was not surprising. The ultimate purpose of phototherapy is to prevent, kernicterus and kernicterus is a rare event. Moreover, factors other than the absolute level of total serum bilirubin are important additional risk factors for kernicterus- for example, prematurity or co-existence of illnesses such as sepsis, perinatal asphyxia and acidosis. For these reasons it was impossible to devise strategies that would accurately determine ‘correct’ thresholds for treatment.

Despite this, an aim of early intervention for hyperbilirubinaemia is to prevent the need for subsequent more invasive treatments. Phototherapy is commonly used to treat

Page 24 UK NSC External Review hyperbilirubinaemia. The aim of phototherapy is to expose the baby’s skin to as much light as possible. The current NICE guidelines recommend that phototherapy is continued until bilirubin levels are low enough (serum bilirubin levels are tested once every 6 to 12 hours after bilirubin levels have started to fall). If possible phototherapy is stopped for 30 minutes every 3 to 4 hours to allow feeding. Exchange transfusion is used to treat extreme hyperbilirubinaemia or rapidly rising bilirubin levels that are not responding to phototherapy treatment.

Phototherapy The NICE evidence review for the neonatal jaundice guideline concluded that there was a large and clear body of evidence that phototherapy is an effective treatment for lowering, and stopping the rise of, bilirubin levels in neonates and can reduce the need for subsequent exchange transfusion, a more invasive treatment.2

There have been a number of small RCTs published on phototherapy since the NICE systematic search, these have largely centred on optimising the effectiveness of phototherapy through investigating the effect of the type of light source used,34,35 the frequency of phototherapy,36,37 skin exposure to the light according to how the baby is positioned38 and light direction39 on reducing bilirubin levels. None of these subsequent studies contradict the conclusions that conventional phototherapy is an effective treatment for hyperbilirubinaemia.

NICE assessed the evidence for adverse effects associated with phototherapy including DNA damage, skin cancer, trans-epidermal water loss, heart rate variability, vasodilation and patent ductusarteriosus. The evidence was generally of poor quality.

NICE identified four small studies of mixed quality that indicated phototherapy was associated with increased trans-epidermal water loss in babies undergoing treatment,2, however, they gave reassurance that this was not a clinically important issue if good clinical practice was followed. Evidence from two poor, and one good quality study linked phototherapy to an increase in molecular level DNA damage were cited by NICE.2 There was no evidence to suggest that these small scale molecular changes in DNA could lead to any clinically significant adverse events.

Concerns around the potential impact of interrupting breastfeeding during phototherapy treatment have also been raised. While no studies were identified that addressed breastfeeding and phototherapy directly, clear guidance on feeding and hydration during different types of phototherapy have been produced to address this concern.2

No studies have ruled out the possibility of significant but rare and or late adverse effects as a result of undergoing phototherapy as a baby. No studies identified in our updated search described adverse events associated with phototherapy.

Exchange transfusion

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NICE reviewed 22 studies that assessed the direct effectiveness of exchange transfusion in reducing mortality or incidence of kernicterus. However, the overall quality of the studies was determined to be poor. Using the limited quality evidence available,2 NICE concluded that double volume exchange transfusion carried out by experienced health professionals is a relatively safe and effective procedure for babies at risk of kernicterus from severe hyperbilirubinaemia.2

The best quality study reporting adverse events associated with exchange transfusion identified in the NICE evidence review was an old (published in 1985) yet large study in the USA.40 This identified that of 190 babies receiving 331 exchange transfusions, transient bradycardia was observed in 4.2% of babies treated. Transient cyanosis (1.6%); transient vasospasm (1.0%); and apnoea and/or bradycardia requiring treatment (3.7%) were also reported. The most common adverse effects of exchange transfusion reported from two additional poor quality non- comparative studies identified by the NICE review were; thrombocytopenia, hypocalcaemia, catheter malfunction, hypotension, venous thrombosis, hypokalaemia and hypoglycaemia.41,42 Between 1.58% and 2.83% of babies that received exchange transfusions (single or multiple) in these three studies died. 41,42,40 As some infants undergo multiple exchange transfusions the mortality associated with each individual treatment will be lower than the figures quoted above.

A group of small studies published since the NICE systematic search broadly confirms the most common adverse events identified above.43-47 No deaths were attributable to exchange transfusion therapy in these five studies but this may be because they were of insufficient size (range N=16 to N=150) to detect deaths given a mortality rate of between 1-2% as indicated above.

Other treatments The evidence supports the current clinical practice of using intravenous immunoglobulin (IVIG) alongside phototherapy in babies with Rhesus and ABO haemolytic disease.2 This practice is also in line with recent guidance from the Department of Health published in 200848 and supported by a recent literature review which was not cited by NICE.49 The evidence for effectiveness of clofibrate combined with PT in neonatal jaundice is relatively strong but is confined mainly to studies done in Iran, and so may not be generalisable to the UK NICE assessed six studies and a further two studies assessing clofibrate were published after NICE’s systematic search .2,50,51 NICE noted that studies of clofibrate in adults reported significant adverse effects and concluded that clofibrate should not be recommended until more research is available to demonstrate safety and efficacy. NICE also recommended that the following should also not be used to treat hyperbilirubinaemia: agar, albumin, barbiturates, charcoal, cholestyramine, D-penicillamine, glycerine, manna, metalloporphyrins, riboflavin, traditional Chinese medicine, acupuncture, homeopathy. Sunlight was additionally not recommended as a treatment for hyperbilirubinaemia. Criteria 10 met? Partly, bilirubin lowering treatments are available and early non-invasive light therapy can reduce the need for more invasive exchange transfusion if given early. However, the cut-offs for treatment were reached by consensus and it is not clear whether these are the ‘correct’ thresholds to prevent cases of kernicterus.

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11. There should be agreed evidence based policies covering which individuals should be offered treatment and the appropriate treatment to be offered The NICE guidance comments that “it was impossible to devise studies that would accurately determine ‘correct’ thresholds for treatment” but acknowledged that therapeutic thresholds are important.2

In light of the lack of evidence, the current NICE guidance on treatment thresholds was produced by the NICE guidance development group (GDG) through an informal consensus process for both phototherapy and exchange transfusion. The primary aim of the consensus agreement was to choose a threshold with a wide margin of safety, with the threshold for phototherapy well below that for exchange transfusion as phototherapy has a good safety profile relative to exchange transfusion. However, avoiding unnecessary phototherapy was also considered. The treatment thresholds are well below the BPSU criteria for severe hyperbilirubinaemia outlined in its surveillance programme.5

The recommended thresholds take into account known variations in serum bilirubin levels due to gestational age and the rapid rise of bilirubin in the first few days after birth. They are similar to the widely publicised threshold guidance produced by the American Academy of Pediatrics (AAP) in 2004.9

A difference of opinion over the appropriate threshold levels for phototherapy treatment was highlighted by a large study that reviewed the records of 1,441 cases of neonatal hyperbilirubinaemia treated with phototherapy in the Republic of Ireland from 1998-2006,52 539 of these infants were of term gestation. The study revealed that in Ireland between 1998 and 2006 around 2.5% of all infants born were receiving phototherapy during their post natal period. They highlighted that the AAP 2004 guidelines had a lower threshold for starting phototherapy compared to the 1994 guidelines. The study authors questioned whether having such a low threshold for phototherapy was the most effective way to ensure the prevention of kernicterus. They suggested that monitoring including a suggestion that infants discharged within 3 days of life could have a follow up assessment by a health worker within 48 hours would be a better approach.

The studies published since the Newman and Maisels report do not change the issue that there are a potentially high number of neonates needed to treat to prevent one case of kernicterus due to the rarity of the disease compared with the widespread prevalence and typically benign nature of neonatal jaundice.

NICE has produced treatment thresholds for the management of hyperbilirubinaemia based on an informal consensus process. They are not strongly evidence based and any impact on kernicterus is assumed rather than known and quantifiable Criteria 11 met? Partly, the treatment threshold policy is consensus based rather than evidence based.

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12. Clinical management of the condition and patient outcomes should be optimised in all health care providers prior to participation in a screening programme As mentioned in section 10, the current NICE treatment thresholds for managing neonatal hyperbilirubinaemia are based on informal expert consensus due to a lack of relevant high quality evidence.

Prior to the introduction of the 2010 NICE guidance, a UK study reviewed opinion regarding treatment thresholds for the use of phototherapy and exchange transfusion in treating neonatal hyperbilirubinaemia in 163 hospitals and concluded that there was wide variation in the choice of threshold level, particularly in pre-term babies.53 A similar finding was reported in an English abstract for a Dutch article describing the variability in treatment thresholds in the Netherlands prior to the publication of a guideline.54

We have not identified any studies investigating the management of neonatal hyperbilirubinaemia in the UK since the 2010 NICE guidance was published and, hence, the level of adherence to the current guidance is unknown.

The impact of adherence to neonatal jaundice policies has been highlighted by an American study that assessed implementation of the 2004 AAP guidelines.

The study, based in Texas analysed the records of 698 new-borns over a 7 month period to see how many were followed up at 3-5days of age for hyperbilirubinaemia risk assessment as recommended by the AAP 2004 guidelines.55 The study found that only 37% of eligible infants were followed up within the recommended period including 17 out of the 20 hospitals studied that had routine pre-discharge bilirubin screening policies in place. In addition, the Pilot USA Kernicterus registry highlighted that incidences of kernicterus since 1994 were due to the ineffective implementation of the 1994 AAP guideline.4

These studies serve as a reminder that implementation of recommendations and new guidance can be incomplete and specific attention may be needed to address barriers to compliance.

NICE has produced treatment recommendations but compliance to these guidelines has not been studied. Variations in clinical practice have been reported in other countries and were observed in the UK before the current guidance was introduced. The update search has not identified any studies on educational interventions or audits that would answer the question of whether early identification of severe neonatal jaundice in the community or current guideline based management is optimised or could be further optimised – or on the prevalence of kernicterus since their introduction

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Criteria 12 met? Uncertain, NICE has produced treatment recommendations but adherence to these recommendations has not been studied.

13. There should be evidence from high quality Randomised Controlled Trials that the screening programme is effective in reducing mortality or morbidity. Where screening is aimed solely at providing information to allow the person being screened to make an “informed choice” (e.g. Down’s syndrome, cystic fibrosis carrier screening), there must be evidence from high quality trials that the test accurately measures risk. The information that is provided about the test and its outcome must be of value and readily understood by the individual being screened The updated search did not identify any RCTs addressing this relationship, the new studies we found that have appraised screening programmes have been of a non-comparative design, or before and after studies looking at rates of outcomes before and after the implementation of a screening program. These new studies published since the last policy review have tended to evaluate surrogate outcomes including incidence of hyperbilirubinaemia, which is a major risk factor (surrogate outcome) for developing kernicterus rather than a condition in itself.

The NICE guideline on neonatal jaundice appraised two studies published in 2006 that had assessed before/after rates of hyperbilirubinaemia, phototherapy and exchange transfusion rates with different pre-discharge screening strategies.56,57One of these studies found that universal pre-discharge bilirubin measurements coupled with follow up and parent support led to a decrease in exchange transfusion following failed phototherapy and a decrease in readmission rates for phototherapy. The second study found that the incidence of hyperbilirubinaemia and readmissions for hyperbilirubinaemia decreased with pre-discharge bilirubin screening. The NICE said based on these studies that Low-quality evidence suggests that that universal pre-discharge bilirubin testing may reduce the need for intensive phototherapy and exchange transfusions, and the re admission rate for significant hyperbilirubinaemia. As these studies were considered to be of poor quality NICE said that it was not possible to make a recommendation on pre-discharge bilirubin screening and said this is an area that warrants further research.

Since the publication of the NICE guideline there have been two large studies that have looked at outcomes before and after implementation of screening strategies in a subset of US hospitals and a systematic review that assessed screening studies up to 2007 that have been published since the NICE systematic search.58-60The systematic review concluded that “effects of screening on the rates of bilirubin encephalopathy are unknown. Although screening can predict hyperbilirubinaemia, there is no robust evidence to suggest that screening is associated with favourable clinical outcomes” .Other studies published since the NICE guideline have demonstrated that the introduction of screening leads to a reduction in the number of re- admissions to hospital for neonatal hyperbilirubinaemia.61,62

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The largest of the two American studies was a North American cohort study following over one million births over 5 years showed that pre discharge bilirubin screening decreased the incidence of severe >342 µmol/L, extreme 428 to 511 µmol/L and hazardous >513 µmol/L bilirubin levels in neonates.59 After the introduction of a comprehensive screening program, the incidence of infants with extreme bilirubin levels declined from 43 per 100,000 to 27 per 100,000, and the incidence of infants with hazardous total bilirubin levels dropped from 9 per 100,000 to 3 per 100,000 (P=0 .0019 and P=0.0051 respectively).

This reduction was associated with a small but significant increase in phototherapy use over the same 5 year study period from 4.4% in 2004 to 5.1% of all newborns in 2008. They reported no adverse effects associated with the screening program.

The authors caution that other factors might have contributed to the observed reductions which may not be solely due to universal bilirubin testing. Factors such as changing practices and perceptions of staff, additional staff education, improved physician and parental awareness of hyperbilirubinaemia and enhanced lactation support could be strong additional influences contributing to the decreased incidence of hyperbilirubinaemia and re-admission observed.

One recent study cautioned against using pre-discharge bilirubin screening alone to assign future risk of severe hyperbilirubinaemia suggesting that this may provide false reassurance to some families and clinical staff. They found that of 6,220 infants discharged from a new-born nursery, 28 (0.45%) were readmitted for treatment for elevated serum bilirubin levels (>290.7µmol/L). Importantly, 13 of these 28 readmissions (46%) were categorised as low or low- intermediate risk pre-discharge using the Bhutani (1999) nomogram and as such were false negatives using this particular risk assessment tool.63

There is no evidence from RCTs that screening reduces the mortality or morbidity associated with kernicterus. However, non-comparative studies do give low quality evidence suggesting that screening may decrease the incidence of hyperbilirubinaemia, an important risk factor for kernicterus. Further optimisation of pre-discharge risk assessment may be needed to reduce false negative results, and appropriate post-discharge follow up will need to be defined. Criteria 13 met? Not met, no RCTs of the impact of screening on kernicterus were identified.

14. There should be evidence that the complete screening programme (test, diagnostic procedures, treatment/ intervention) is clinically, socially and ethically acceptable to health professionals and the public No studies were identified from the update search that addressed this question directly. Two studies that had implemented screening programs in the USA59 and Canada62 reported that the screening was readily accepted by the majority of nurses, physicians and parents although the methods of assessing this were not well described and may not be robust.

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It is important to note that the USA study used a combination of transcutaneous and serum bilirubin tests whereas the Canadian example primarily used a transcutaneous measure with only babies showing a high or rapidly rising bilirubin level being retested using a serum bilirubin test. The non-invasive nature of a transcutaneous bilirubin test makes it much more likely to be acceptable to parents than a serum bilirubin test requiring a blood sample. The accuracy of using a transcutaneous device compared with a serum sample is discussed in section 5 and 6.

The relative safety of phototherapy and the unknown “safe” cut-offs for kernicterus may lead to an increase in cautious treatments. However, phototherapy although non-invasive may cause undue stress and inconvenience to parents, disrupting their interactions with their child in the first week of life if not-indicated. In 2009 the US Preventative services Task Force recommendation was that screening of infants for hyperbilirubinaemia to prevent chronic bilirubin encephalopathy should not be recommended due to insufficient evidence for a recommendation to be made.64

Criteria 14 met? Not met

15. The benefit from the screening programme should outweigh the physical and psychological harm (caused by the test, diagnostic procedures and treatment) The balance of benefit and harm of any complete programme has not been evaluated. The two treatments phototherapy and exchange transfusion both carry risks. Of the two treatments for hyperbilirubinaemia, exchange transfusions carry the higher risk of serious adverse events.

As stated in section 10, no studies have ruled out the possibility of significant but rare and or late adverse effects as a result of undergoing phototherapy as a baby.

Physiological jaundice is very common so there is a potential for psychological harm if large numbers of families become overly concerned or alarmed about the risk of kernicterus. Any screening program would naturally have to balance the need to provide relevant information to parents without causing unnecessary anxiety or alarm. Parents are currently already advised about the signs and risks of jaundice.2

The harms (associated with exchange transfusion) are likely to decrease, if earlier phototherapy can lead to fewer exchange transfusions. However it is not clear if this will occur with the introduction of population screening. Rare or late presenting adverse events associated with phototherapy have not been ruled out. Criteria 15 met? Unknown (benefit in terms of impact on kernicterus is unproven)

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16. The opportunity cost of the screening programme (including testing, diagnosis and treatment, administration, training and quality assurance) should be economically balanced in relation to expenditure on medical care as a whole (ie. value for money). Assessment against this criteria should have regard to evidence from cost benefit and/or cost effectiveness analyses and have regard to the effective use of available resource There has been no robust assessment of the economic or cost-effectiveness of implementing a population based bilirubin screening program in the UK or elsewhere. The NICE clinical guideline performed an economic evaluation of testing strategies for hyperbilirubinaemia. The costing template estimated that prior to the publication of the guidelines the percentage of babies identified as jaundiced on visual examination was 60% and of these 20% were tested for jaundice on the basis of this visual examination (total serum bilirubin [TSB] test), the mean number of TSB tests per baby were 1.33. The cost of a TSB test was estimated at £19.23. The costing template estimated that testing would switch to transcutaneous measurements and that all babies with visible jaundice would have transcutaneous measurements taken (with an average of 1.33 tests per baby). The percentage of transcutaneous bilirubin tests that would be positive and require a TSB test was estimated as 25%. The cost of performing a TcB test was estimated as costing £1.30. The costing template estimated that 1500 transcutaneous bilirubin meters would be required to implement the guidance. The cost per meter was estimated as £3,400.

There is likely to be cost savings associated with any reduction in neonatal readmissions for hyperbilirubinaemia (see section 13) or any resulting reduction in the incidence of kernicterus and associated care. These savings must be balanced against the cost of implementing all aspects of the screening program and any additional phototherapy use resulting from this.

No robust assessment of the economic or opportunity cost of implementing a kernicterus screening program in the UK or elsewhere was identified in the literature Criteria 16 met? Not met

17. All other options for managing the condition should have been considered (eg. improving treatment, providing other services), to ensure that no more cost effective intervention could be introduced or current interventions increased within the resources available As stated in section 12, no studies have looked at the clinical adherence to the 2010 NICE guidance in the UK and so it is unclear how this has already influenced the management of hyperbilirubinaemia. The guidance states that all babies should be examined for jaundice “at every opportunity especially in the first 72 hours” but it is unknown what “every opportunity” translates to in clinical practice and how much this varies across providers.

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An alternative to introducing a universal kernicterus screening program could be to improve and optimise adherence to the existing NICE recommendations, through educational and other implementation initiatives. It is unclear which approach would be the most cost effective strategy.

Optimising current practice could be an alternative to introducing screening but the cost effectiveness of either approach is unknown. Criteria 17 met? Not met

18. There should be a plan for managing and monitoring the screening programme and an agreed set of quality assessment standards.

Not applicable

19. Adequate staffing and facilities for testing, diagnosis, treatment and programme management should be available prior to the commencement of the screening programme Not applicable

20. Evidence-based information, explaining the consequences of testing, investigation and treatment, should be made available to potential participants to assist them in making an informed choice Physiological jaundice is very common while pathological jaundice is very rare. A balance must be sought to adequately inform new parents of relevant risks without causing alarm or overloading them with information at the expense of other important perinatal advice, such as the importance of breastfeeding.

To accompany its guideline NICE has produced an evidence based factsheet for parents explaining how to check for signs of jaundice in their baby, what to do if their baby has jaundice and explaining about treatments for jaundice. This is available from: http://guidance.nice.org.uk/CG98/Factsheet/pdf/English Criteria 17 met? Not met. Only available for the tests used in clinically indicated contexts.

21. Public pressure for widening the eligibility criteria for reducing the screening interval, and for increasing the sensitivity of the testing process, should be anticipated. Decisions about these parameters should be scientifically justifiable to the public There is some public pressure for improving detection of kernicterus. Since the publication of the NICE guidelines a case of a boy who developed kernicterus was reported by the BBC News. This case was reported to have occurred as a consequence of advice given to the boys’ parents that was not in keeping with NICE guidance.http://www.bbc.co.uk/news/uk-england-lancashire- 13862910. Societal and clinical efforts may be best directed towards appropriate implementation of NICE guideline rather than the initiation of a universal screening programme.

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22. If screening is for a mutation the programme should be acceptable to people identified as carriers and to other family members Not applicable

Conclusions

Kernicterus is a rare but serious condition caused by bilirubin neurotoxicity in newborns. Although hyperbilirubinaemia is a risk factor for kernicterus, other factors may be involved. It is currently not possible to predict which of the 60% of newborns with jaundice will resolve naturally while at the same time identifying approximately 1 case per 100,000 whose bilirubin will rise to a level sufficient to cause encephalopathy in that individual. There is no clear cut-off level of bilirubin that accurately identifies a cohort which will progress to kernicterus, and cases have been observed across a range of bilirubin concentrations. It is unclear whether there are additional risk factors which increase the likelihood that an infant with hyperbilirubinaemia will develop kernicterus.

What is known is that early intervention with phototherapy, a non-invasive treatment, can lower bilirubin levels and prevent more intensive treatments being required. Monitoring of neonatal jaundice and clear treatment algorithms has the potential to treat infants early and reduce the number who will develop clinically significant hyperbilirubinaemia. NICE has recently produced guidance which recommends monitoring jaundice in the first 72 hours of birth, particularly in the first 24 hours, the use of transcutaneous or serum bilirubin measurements and appropriate cut-offs for phototherapy and exchange transfusion. The initial assessment of the newborn is for visual signs of jaundice. This is followed by tests to measure bilirubin levels in clinically indicated circumstances. The guidelines are expected to increase the proportion of apparently jaundiced babies that receive bilirubin measurements from 20% to 100%.

Presently NICE does not recommend a pre-discharge risk assessment and clinically significant hyperbilirubinaemia may occur at home within the first week of life in some infants. If the guidance is followed bilirubin levels will only be measured in newborns with visual signs of jaundice rather than in all children. NICE does recommend identification of neonates who are at risk using clinical risk factors. NICE does not recommend the use of pre-discharge bilirubin levels to predict risk of hyperbilirubinaemia as current risk models are not thought to be generalizable to UK newborns. This is an area in which NICE recommends further research.

Although the BPSU has monitored severe hyperbilirubinaemia (> 510 µmol/L), further information on the distribution of UK bilirubin levels is needed to broaden the knowledge base on the natural history of kernicterus. There still remains uncertainty on an appropriate marker for risk of developing kernicterus and whether current indications for bilirubin lowering treatments would prevent new cases of

Page 34 UK NSC External Review kernicterus. These uncertainties prohibit the recommendation of a screening programme for kernicterus.

Implications for policy There is no new evidence that suggests that NSC policy needs to change.

Implications for research Adherence to the NICE guideline could be assessed alongside the parent experience of neonatal care. In particular the current practice of follow up visits for newborns after discharge could be assessed and the degree to which jaundice can be identified accurately at the 5- day heel prick visit.

Previous surveillance of UK and Irish babies with severe hyperbilirubinaemia has been performed; however prospective follow up of a UK cohort of babies with lower bilirubin levels should be performed to better describe the age dependent distribution of bilirubin levels in a UK population.

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Methodology Sources searched: Medline, Embase, Cochrane Library.

Dates of search: Medline 2006- January Week 4 2011; Embase 2006-2011 Week 05, Cochrane Library 2011 Issue 1.

Search strategy. Medline (OVID interface) 1 hyperbilirubinemia, neonatal/ 2 Kernicterus/ 3 1 or 2 4 limit 3 to yr="2006 -Current"

Embase (OVID interface) 1 kernicterus/ 2 hyperbilirubinemia/ 3 newborn/ 4 neonat*.mp. 5 (1 or 2) and (3 or 4) 6 limit 5 to yr="2006 -Current"

Cochrane Library (Wiley Online Library interface) #1 MeSH descriptor Hyperbilirubinemia, Neonatal, this term only #2 hyperbilirubin* #3 (neonat* or newborn) #4 MeSH descriptor Kernicterus explode all trees #5 kernicterus #6 (( #1 OR #2 OR #4 OR #5 ) AND #3), from 2006 to 2011

Results All results were downloaded into an Access database, and 213 duplicates removed. A total of 1024 citations remained.

Database No. citations Exclusive retrieved Medline 375 374 Embase 760 571 Cochrane Library 102 79 Total = 1237 Total = 1024

4 articles were removed that had been considered in the 2006 review. The title and abstracts of the remaining citations, and where necessary and available the full text, were examined for relevance to neonatal hyperbilirubinaemia screening. Articles commenting on other papers are listed with the original paper. 370 citations remained, and have been classified as follows:

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Category No. of citations Systematic reviews and meta- 4 analyses Guidelines 12 Non-systematic reviews 52 Prevalence of kernicterus 16 Risk factors for kernicterus 15 Risk factors for hyperbilirubinaemia 55 Tests for identification/screening 85 Treatment 114 Screening programme 17

Total 370

Quality We performed a first pass appraisal of each abstract followed by a retrieval of selected full text papers from the updated search. An overview of the most informative and relevant references regarding the individual screening criteria is given below. Guidelines and systematic reviews of the evidence were prioritised alongside high quality study designs such as randomised controlled trials. We excluded narrative reviews, conference abstracts and non-English publications. We also prioritised studies from the UK, or from countries where the demographics were likely to be similar to the UK. For some criteria we have presented a summary of the systematic review used by NICE to produce guidelines to test and treat for clinically significant hyperbilirubinaemia (as the guidance was published since the last policy review) and have supplemented this with articles that have been published since the NICE guidelines. The NICE clinical guidelines on Neonatal Jaundice performed a systematic review of the literature including articles up to June 2009. Articles in the updated search that were reviewed for the NICE guidelines, were not for the most part reviewed separately unless they were considered to contain additional information for other criteria not already assessed by NICE.

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